Triethylamine → N-[(6S,9R)-6-(2,3-Difluorophenyl)-3-(1-hydroxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide

HRID 1664949Notes

Reaction equation

HRID 1664949 reaction equation
C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]2[C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][N:26]=[C:10]12.[C:31]([N:38]1[CH:42]=[CH:41]N=[CH:39]1)(N1C=CN=C1)=[O:32].[C:43]1(=[O:53])[C:47]2(CCNC[CH2:48]2)[CH2:46][CH2:45][NH:44]1>O1CCCC1.ClCCl>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]2[C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:25][N:26]=[C:10]2[C@H:9]([NH:8][C:31]([N:38]2[CH2:39][CH2:48][C:47]3([C:43](=[O:53])[NH:44][CH2:45][CH2:46]3)[CH2:41][CH2:42]2)=[O:32])[CH2:15][CH2:14]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 682631,1'-Carbonyldiimidazole2×HCID 222250112,8-Diazaspiro[4.5]decan-1-oneHCID 674393392-[(6S,9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl]propan-2-ol

Product 1

HCID 59722546N-[(6S,9R)-6-(2,3-Difluorophenyl)-3-(1-hydroxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamideYield 78%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

Triethylamine (18 μL, 0.126 mmol) was added to a solution of the bis hydrochloride salt of 2-[(6S,9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl]propan-2-ol (20 mg, 0.051 mmol) and 1,1′-carbonyldiimidazole (14 mg, 0.09 mmol) in tetrahydrofuran (1.0 mL) at 0° C. After 10 min, additional 1,1′-carbonyldiimidazole (8.0 mg, 0.05 mmol) was added. After 30 min, the hydrochloride salt of 2,8-diazaspiro[4.5]decan-1-one (12 mg, 0.06 mmol) and dichloromethane (1.0 mL) were added and the mixture was heated to 60° C. After 16 h, the reaction was concentrated. Purification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (20 mg). MS 503.2570 (M+1).

Workup

  1. waitAfter 30 min
  2. waitAfter 16 h
  3. concentrationthe reaction was concentrated
  4. customPurification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-24395d295fe14f12b8a8d1f07dbb0d25
Source dataset
uspto-grants-2011_10
Patent number
US08039460B2

Reaction notes

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